Channelpedia

Nav1.4

Description: sodium channel, voltage-gated, type IV, alpha subunit
Gene: Scn4a     Synonyms: nav1.4, scn4a

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Introduction

SCN4A (also known as HYPP; SkM1; HYKPP; NAC1A; HOKPP2; Nav1.4; Na(V)1.4) encodes Nav1.4, a member of the sodium channel alpha subunit gene family. It is expressed in skeletal muscle, and mutations in this gene have been linked to several myotonia and periodic paralysis disorders. http://www.ncbi.nlm.nih.gov/gene/6329

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Gene

RGD ID Chromosome Position Species
3636 10 95710710-95760323 Rat
11268 11 106179907-106210704 Mouse
732165 17 62015914-62050278 Human

Scn4a : sodium channel, voltage-gated, type IV, alpha subunit

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Transcript

Acc No Sequence Length Source
NM_013178 n/A n/A NCBI
NM_133199 n/A n/A NCBI
NM_000334 n/A n/A NCBI
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Ontology

Accession Name Definition Evidence
GO:0001518 voltage-gated sodium channel complex A sodium channel in a cell membrane whose opening is governed by the membrane potential. IEA
GO:0016021 integral to membrane Penetrating at least one phospholipid bilayer of a membrane. May also refer to the state of being buried in the bilayer with no exposure outside the bilayer. When used to describe a protein, indicates that all or part of the peptide sequence is embedded in the membrane. IEA
GO:0016020 membrane Double layer of lipid molecules that encloses all cells, and, in eukaryotes, many organelles; may be a single or double lipid bilayer; also includes associated proteins. IEA
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Interaction

Calmodulin

CaM (Calmodulin) regulates the current density of NaV1.4. Association with CaM is important for functional expression of NaV1.4. Disrupting the interaction between CaM and the C terminus of NaV1.4 reduced current amplitude by 99%. Calmodulin also was able to modulate the inactivation kinetics of Nav1.6, but not Nav1.4, currents in a calcium-dependent manner. [53].

(Calmodulin, a 16.7 kDa protein that is expressed in virtually all eukaryotic cells, can induce changes in target proteins via its binding per se and in response to changes in calcium concentration [823]. For example, the activity of sodium channels in Paramecium tetraurelia is CaM-dependent [824], and CaM plays a crucial role in the modulation of calcium channels [825].)

Ranolazine

Ranolazine is an antianginal and anti-ischemic drug that is used in patients with chronic angina [833]. Ranzoline blocks Na+ currents of Nav1.4. Both muscle and neuronal Na+ channels are as sensitive to ranolazine block as their cardiac counterparts. At its therapeutic plasma concentrations, ranolazine interacts predominantly with the open but not resting or inactivated Na+ channels. Ranolazine block of open Na+ channels is via the conserved local anesthetic receptor albeit with a relatively slow on-rate. [827]

Tetrodotoxin

Nav1.4 is tetrodotoxin sensitive (non selective). [834]

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Protein

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Structure

The skeletal muscle a subunit functions as ion-conducting channel and consists of large polypeptides (1700–2000 amino acids) that fold into four highly homologous somains (repeats I-IV) containing six transmembrane segments each (S1-S6). The S6 transmembrane segments and the S5- S6 loops form the ion selective pore, and the S4 segments contain positively charged residues conferring voltage dependence to the protein. The repeats are connected by intracellular loops; one of them, the III-IV linker, contains the supposed inactivation particle of the channel. When inserted in the membrane, the four repeats of the protein fold to generate a central pore. [1403],[815]

Amino acid Ile-1575 in the middle of transmembrane segment 6 of domain IV (DIV-S6) in the adult rat skeletal muscle isoform of the voltage-gated sodium channel (rNaV1.4) may act as molecular switch allowing for interaction between outer and inner vestibules. [829]

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Distribution

Nav1.4 channels are located in the sarcolemma and T-tubular membranes, with a high density near the endplate of the muscle cell. [1406]

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Expression

Nav1.4 is expressed at high levels in adult skeletal muscle, at low levels in neonatal skeletal muscle, and not at all in brain or heart[834].

Relative mRNA expression levels of Nav1.4, analyzed by RT-PCR, were significantly higher in ovarian cancers cells compared with normal ovarian tissues and relative mRNA expression levels Nav1.4 were significantly increased in highly metastatic ovarian cancer cells (Caov-3 and SKOV-3) compared with low-metastatic ovarian cancer cells (Anglne). [830]

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Functional

NaV1.4 is responsible for the generation and propagation of action potentials that initiate muscle contraction.

Channelopathies

Mutations in NaV1.4 channels increase channel activity by impairing fast and/or slow inactivation causing hereditary sodium channelopathies of skeletal muscle such as [[1390]:
* Hyperkalaemic periodic paralysis
* Hypokalaemic periodic paralysis
* Paramyotonia congenital
* Potassium-aggravated myotonia
* Congenital myasthenic syndrome
* Muscle stiffness [826]

VSGC blockers such as mexiletine, flecainide and other lidocaine analogues can reduce repetitive firing of action potential because of their use-depended properties, a mechanism that leads to a preferential action on channels with pathogenic gain-of-function mutations. These blockers reduce muscle stiffness in potassium-aggravated myotonia and paramyotonia congenita by promoting the inactivated state of NaV1.4 by inducing a hyperpolarized shift in steady-state inactivation and by prolonging recovery time from inactivation. Symptoms of muscle weakness are often caused by other pathogenic factors and cannot be treated sufficiently with VGSC blockers [[1390].

Expression of skeletal muscle sodium channel (Nav1.4) prevents reperfusion arrhythmias in murine heart. [[828]

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Kinetics

In addition to fast and slow inactivation there is a third type of inactivation named ultra-slow inactivation. This process was described inNav1.4 when the alanine in position 1529 (A1529) is replaced by aspartate (D) in the domain IVP-loop. Binding of the fast inactivating particle inhibits this process. This result demonstrates that there are interactions (mostly, allosteric modulation) among the different inactivation events. [1376], [1405]

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Model

References

823

Chin D et al. Calmodulin: a prototypical calcium sensor.
Trends Cell Biol., 2000 Aug , 10 (322-8).

825

Zühlke RD et al. Calmodulin supports both inactivation and facilitation of L-type calcium channels.
Nature, 1999 May 13 , 399 (159-62).

834

Goldin AL Resurgence of sodium channel research.
Annu. Rev. Physiol., 2001 , 63 (871-94).

852

Bennett ES et al. Voltage-gated Na+ channels confer invasive properties on human prostate cancer cells.
Pflugers Arch., 2004 Mar , 447 (908-14).

1403

Jurkat-Rott K et al. Paroxysmal muscle weakness: the familial periodic paralyses.
J. Neurol., 2006 Nov , 253 (1391-8).

1404

Biswas S et al. Calmodulin regulation of Nav1.4 current: role of binding to the carboxyl terminus.
J. Gen. Physiol., 2008 Mar , 131 (197-209).

1405

Goldin AL Mechanisms of sodium channel inactivation.
Curr. Opin. Neurobiol., 2003 Jun , 13 (284-90).

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Credits

To cite this page: [Contributors] Channelpedia https://channelpedia.epfl.ch/ionchannels/123/ , accessed on [date]